SEPSIS BULLETIN 4 January 2019 - Oxford Patient Safety Collaborative

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                                         SEPSIS BULLETIN
                                           4 January 2019
 Neonatal, paediatric and maternal sepsis                      Adult sepsis (cont.)

 Effects of prebiotics on sepsis, necrotizing enterocolitis,   The 2018 Surviving Sepsis Campaign’s Treatment
 mortality, feeding intolerance, time to full enteral          Bundle: When Guidelines Outpace the Evidence
 feeding, length of hospital stay, and stool frequency in      Supporting Their Use
 preterm infants: a meta‐analysis.
                                                               Spiegel, R. et al
 Chi, C. et al
                                                               Ann Emerg Med. 2018 Aug 30. pii: S0196‐
 European journal of clinical nutrition December 19,           0644(18)30607‐3
                                                          Although well intentioned, the current sepsis bundles
 Prebiotics are increasingly recognized as an effective   and the potential penalties associated with
 measure to promote health and prevent adverse health noncompliance lay a heavy weight on ED care absent
 outcomes in preterm infants. We aimed to                 evidence that a net benefit will follow. The proposed
 systematically review the randomized controlled trials   Surviving Sepsis Campaign abbreviated bundle
 (RCTs) in this area. The results showed that the use of  heightens the burden by further restricting the time
 prebiotics with preterm infants is safe and can decrease allotted for the identification and treatment of
 the incidence of sepsis, mortality, length of hospital   patients with suspected sepsis, all without any
 stay, and time to full enteral feeding but not NEC.      evidence of benefit or knowledge of the logistic
                                                          consequences or cost. A more thoughtful approach to
                                                          both the identification and management of patients
                                                          with sepsis is needed, one that engages all
Sepsis prediction during outbreaks at neonatal               stakeholders and experts, including the emergency
intensive care units through body surface screening for      medicine clinicians who treat most patients
Gram‐negative bacteria: systematic review and meta‐          hospitalized with sepsis and who will be responsible
analysis.                                                    for implementing these recommendations. A better
                                                             strategy will identify more meaningful time stamps,
Harder, T. et al
                                                             focus less on the exact volume of fluid administered,
BMC research notes, December 22, 2018, Vol.11(1),            and concentrate on identifying the subgroup of septic
p.917                                                        patients who will benefit from timely, appropriate care
                                                             while limiting the diagnostic noise and logistic burdens
This systematic review focusses on the prognostic            that come with oversensitive screening tools.
accuracy of neonatal body surface screening during
outbreaks caused by Gram‐negative bacteria for
prediction of sepsis. In a previous systematic review we
                                                             A Comparison of the Quick Sequential (Sepsis‐Related)
reported that only limited evidence of very low quality
                                                             Organ Failure Assessment Score and the National Early
exists regarding the predictive value of this screening
                                                             Warning Score in Non‐ICU Patients With/Without
under routine conditions. We aimed to investigate
whether this is different in outbreak settings. Extending
a previously published systematic review, we show            Redfern, O.C. et al
here that in contrast to routine settings sensitivity of
                                                             Critical Care Medicine: December 2018 ‐ Volume 46 ‐
body surface screening for sepsis prediction is very
                                                             Issue 12 ‐ p 1923–1933
high, while specificity is still insufficient. Surface
screening appears to be a useful component of bundles        The Sepsis‐3 task force recommended the quick
of interventions used during outbreaks, but the              Sequential (Sepsis‐Related) Organ Failure Assessment
evidence base is still limited.                              score for identifying patients with suspected infection
                                                             who are at greater risk of poor outcomes, but many
                                                             hospitals already use the National Early Warning Score
Immunologic biomarkers for diagnostic of early‐onset         to identify high‐risk patients, irrespective of diagnosis.
neonatal sepsis.                                             We sought to compare the performance of quick
                                                             Sequential (Sepsis‐Related) Organ Failure Assessment
Memar, M.Y. et al
                                                             and National Early Warning Score in hospitalized, non‐
The journal of maternal‐fetal & neonatal medicine            ICU patients with and without an infection. The
January 2019, Vol.32(1), pp.143‐153                          National Early Warning Score outperforms the quick
                                                             Sequential (Sepsis‐Related) Organ Failure Assessment
Accurate identification of early onset neonatal sepsis       score, irrespective of infection status. These findings
(EOS) is challenging. Blood culture has been considered      suggest that quick Sequential (Sepsis‐Related) Organ
as a gold standard method but the identification of EOS      Failure Assessment should be re‐evaluated as the
is intricate by a high false‐negative results. This review   system of choice for identifying non‐ICU patients with
provides an overview of biomarkers as indicators for         suspected infection who are at greater risk of poor
the diagnosis of EOS. There is an affluence of studies       outcome.
appraising diagnostic indicators in the identification of
EOS. Acute‐phase reactants, cytokines, and cell surface
antigens have been investigated as indicators for EOS,
                                                             A Retrospective Review of the Sepsis Definition after
but none of them are presently in routine clinical
                                                             Publication of Sepsis‐3.
setting. Despite the promising data for some
immunologic biomarkers, present evidence shows that          Braun, Derek
none of them can constantly diagnose 100% of
                                                             The American journal of medicine, November 22,
infections. IL‐6 is the most potent marker for evaluation
of EOS prognosis. Procalciton (PCT) and C‐reactive
protein (CRP) are appropriate indicators for the             Two and a half years after the introduction of Sepsis‐3,
detection and monitoring of antibiotics therapy. A           clinicians continue not to document Sequential Organ
panel of sepsis biomarkers along with presently routine      Failure Assessment (SOFA) scores. The purpose of this
tests will make easy earlier identification, appropriate   review is to determine if the Third International
management, and improved outcome may be more               Consensus Definitions for Sepsis and Septic Shock
efficient than single indicator.                           (Sepsis‐3) were being utilized in defining sepsis in the
                                                           clinical setting. There continue to be variations in what
                                                           standard is accepted by both commercial payers and
Screening for colonisation with gentamicin‐resistant       the Centers for Medicare and Medicaid (CMS) in
Gram‐negative organisms on the neonatal unit: does         diagnosing sepsis. Due to Sepsis‐3 criteria not being
positive screening predict sepsis?                         accepted by CMS or the Infectious Disease Society of
                                                           America, along with it not being able to be
Walker, O. et al                                           operationalized for use in the clinical setting, it is
Archives of disease in childhood. Fetal and neonatal       recommended to continue utilizing systemic
edition, January 2019, Vol.104(1), pp.F113‐F114            inflammatory response syndrome criteria plus
                                                           infection while Sepsis‐3 continues to be evaluated. It
At our tertiary‐level neonatal unit, surface swabs have    will also allow for some time to study any effect it may
been taken weekly to screen for gentamicin‐resistant       have on patient outcomes. There is also a need for a
GNB. We conducted a retrospective analysis to              uniform definition of sepsis.
investigate whether colonisation screening in our unit
is effective at predicting LOS.
                                                           Early Post‐Intensive Care Syndrome among Older Adult
                                                           Sepsis Survivors Receiving Home Care.
Severe group A streptococcal infections in mothers and
their newborns in London and the South East, 2010–         Riegel, B. et al
2016: assessment of risk and audit of public health        Journal of the American Geriatrics Society, November
management                                                 30, 2018
Leonard, A. et al                                         New or worsened disabilities in functional, cognitive,
BJOG : an international journal of obstetrics and         or mental health following an intensive care unit (ICU)
gynaecology, January 2019, Vol.126(1), pp.44–53.          stay are referred to as post‐intensive care syndrome
                                                          (PICS). PICS has not been described in older adults
Are public health guidelines being followed in the        receiving home care. Our aim was to examine the
management of mothers and their newborns to reduce relationship between length of ICU stay and PICS
the risk of iGAS infection? We describe cases of invasive among older adults receiving home care. We expected
group A Streptococcus (iGAS) in mothers or neonates       that patients in the ICU for 3 days or longer would
and assess management according to national               demonstrate significantly more disability in all three
guidelines, which recommend administering antibiotics domains on follow‐up than those not in the ICU. A
to both mother and neonate if either develops iGAS        secondary aim was to identify patient characteristics
infection within 28 days of birth and investigation of    increasing the odds of disability. Older adults receiving
clusters in maternity units. iGAS infection remains a     home care who develop sepsis and are in an ICU for 3
potential postpartum risk. Prophylaxis among neonates days or longer, are likely to develop new or worsened
and storage of isolates from maternity cases can be       physical disabilities. Whether these disabilities remain
improved.                                                 after the early post‐discharge phase requires further

Genetic polymorphisms and sepsis in premature
neonates.                                                  Sepsis: developing new alternatives to reduce
Esposito, S. et al                                         neuroinflammation and attenuate brain injury.

PloS one, 2014, Vol.9(7), p.e101248                        Meneses G. et al

Identifying single nucleotide polymorphisms (SNPs) in      Ann N Y Acad Sci. 2018 Nov 29.
the genes involved in sepsis may help to clarify the
pathophysiology of neonatal sepsis. The aim of this          Sepsis occurs when a systemic infection induces an
study was to evaluate the relationships between sepsis       uncontrolled inflammatory response that results in
in pre‐term neonates and genes potentially involved in       generalized organ dysfunction. The exacerbated
the response to invasion by infectious agents. The           peripheral inflammation can induce, in turn,
results show that genetic variability seems to play a        neuroinflammation which may result in severe
role in sepsis in pre‐term neonates by influencing           impairment of the central nervous system (CNS).
susceptibility to and the severity of the disease, as well   Indeed, the ensuing blood‐brain barrier disruption
as the risk of having disease due to specific pathogens.     associated with sepsis promotes glial activation and
                                                             starts a storm of proinflammatory cytokines in the CNS
                                                             that leads to brain dysfunction in sepsis survivors.
Earlier and more targeted treatment of neonatal sepsis.      Endotoxic shock induced in mice by peripheral
                                                             injection of lipopolysaccharides closely resembles the
Özenci, V. et al                                             peripheral and central inflammation observed in
Acta paediatrica (Oslo, Norway : 1992), January 2019,        sepsis. In this review, we provide an overview of the
Vol.108(1), pp.169‐170                                       neuroinflammatory features in sepsis and of recent
                                                             progress toward the development of new anti‐
Neonatal sepsis occurs in 1–2 of the 1000 live born          neuroinflammatory therapies seeking to reduce
neonates and accounts for 3‐5% of deaths in term and         mortality and morbidity in sepsis survivors.
more than 30% in extremely preterm infants. These
mortality rates due to neonatal infections are
unacceptably high. Immediate and targeted antibiotic         Autophagy and skeletal muscles in sepsis.
treatment is crucial in order to improve survival in this
vulnerable population. Pilot study.                          Mofarrahi, M. et al

                                                             PloS one, 2012, Vol.7(10), p.e47265

Which biomarkers reveal neonatal sepsis?                     Mitochondrial injury develops in skeletal muscles
                                                             during the course of severe sepsis. Autophagy is a
Wang K. et al                                                protein and organelle recycling pathway which
PLoS One. 2013 Dec 18;8(12):e82700.                          functions to degrade or recycle unnecessary,
                                                             redundant, or inefficient cellular components. No
We address the identification of optimal biomarkers for      information is available regarding the degree of sepsis‐
the rapid diagnosis of neonatal sepsis. We employ both       induced mitochondrial injury and autophagy in the
canonical correlation analysis (CCA) and sparse support      ventilatory and locomotor muscles. This study tests
vector machine (SSVM) classifiers to select the best         the hypotheses that the locomotor muscles are more
subset of biomarkers from a large hematological data         prone to sepsis‐induced mitochondrial injury,
set collected from infants with suspected sepsis from        depressed biogenesis and autophagy induction
Yale‐New Haven Hospital's Neonatal Intensive Care            compared with the ventilatory muscles. We conclude
Unit (NICU). CCA is used to select sets of biomarkers of     that locomotor muscles are more prone to sepsis‐
increasing size that are most highly correlated with         induced mitochondrial injury, decreased biogenesis
infection. The effectiveness of these biomarkers is then     and increased autophagy compared with the
validated by constructing a sparse support vector            ventilatory muscles and that autophagy in skeletal
machine diagnostic classifier. We find that the              muscles during sepsis is regulated in part through the
following set of five biomarkers capture the essential       NFκB transcription factor.
diagnostic information (in order of importance): Bands,
Platelets, neutrophil CD64, White Blood Cells, and Segs.
Further, the diagnostic performance of the optimal set       Interleukin 38 Protects Against Lethal Sepsis.
of biomarkers is significantly higher than that of
isolated individual biomarkers. These results suggest an     Xu, F. et al
enhanced sepsis scoring system for neonatal sepsis that
                                                             The Journal of infectious diseases, August 24, 2018,
includes these five biomarkers. We demonstrate the
                                                             Vol.218(7), pp.1175‐1184
robustness of our analysis by comp
Interleukin 38 (IL‐38) is the most recently
                                                             characterized cytokine of the interleukin 1 family.
Mupirocin for Staphylococcus aureus Decolonization of
                                                             However, its role in sepsis remains unknown. Our
Infants in Neonatal Intensive Care Units.
                                                             findings suggest that IL‐38 attenuates sepsis by
Kotloff, K.L.1et al                                          decreasing inflammation and increasing bacterial
                                                             clearance, thus providing a novel tool for antisepsis
Pediatrics. 2019 Jan;143(1). pii: e20181565.                 therapy.
Staphylococcus aureus (SA) is the second leading cause
of late‐onset sepsis among infants in the NICU. Because
colonization of nasal mucosa and/or skin frequently          Sepsis‐The "Gift" That Keeps on Giving, Regardless of
precedes invasive infection, decolonization strategies,      Age.
such as mupirocin application, have been attempted to
                                                             Simpson, S.Q.
prevent clinical infection, but data supporting this
approach in infants are limited. We conducted a phase        Critical care medicine, August 2018, Vol.46(8),
2 multicenter, open‐label, randomized trial to assess        pp.1378‐1380
the safety and efficacy of intranasal plus topical
                                                             There is little doubt that sepsis is an affliction
mupirocin in eradicating SA colonization in critically ill
                                                             associated with aging. Editorial
infants. Application of mupirocin to multiple body sites
was safe and efficacious in eradicating SA carriage
among infants in the NICU; however, after 2 to 3
weeks, many infants who remained hospitalized                A minimal set of physiomarkers in continuous high
became recolonized.                                          frequency data streams predict adult sepsis onset

                                                             van Wyk, F. et al
Management of Neonates Born at ≥35 0/7 Weeks’
Gestation With Suspected or Proven Early‐Onset               International Journal of Medical Informatics,
Bacterial Sepsis                                             02/2019, Vol.122, C, pp.55‐62

Puopolo, K. et al                                            Sepsis is a life‐threatening condition with high
                                                             mortality rates and expensive treatment costs. To
Pediatrics, Dec 2018, Vol.142(6), p.1                        improve short‐ and long‐term outcomes, it is critical to
                                                             detect at‐risk sepsis patients at an early stage. A
The incidence of neonatal early‐onset sepsis (EOS) has
                                                             random forest classifier was trained to discriminate
declined substantially over the last 2 decades, primarily
                                                             between sepsis and non‐sepsis patients. The use of
because of the implementation of evidence‐based
                                                             machine learning algorithms on continuous streams of
intrapartum antimicrobial therapy. However, EOS
                                                             physiological data can allow for early identification of
remains a serious and potentially fatal illness.
                                                             at‐risk patients in real‐time with high accuracy.
Laboratory tests alone are neither sensitive nor specific
enough to guide EOS management decisions. Maternal
and infant clinical characteristics can help identify
newborn infants who are at risk and guide the                Exploring the Pathways Revealed by International
administration of empirical antibiotic therapy. The          Sepsis Benchmarking.
incidence of EOS, the prevalence and implications of         Walkey, A.J.
established risk factors, the predictive value of
commonly used laboratory tests, and the uncertainties        Critical care medicine, January 2019, Vol.47(1),
in the risk/benefit balance of antibiotic exposures all      pp.135‐137
vary significantly with gestational age at birth.            Editorial

                                                             Sepsis programme successes are responsible for the
Adult sepsis                                                 increased detection of bacteraemia.
Association of Corticosteroid Treatment With                Simmons, M D et al
Outcomes in Adult Patients With Sepsis: A Systematic
                                                            The Journal of hospital infection, January 2019,
Review and Meta‐analysis.
                                                            Vol.101(1), pp.93‐99
Fang, F. et al
                                                            Escherichia coli bacteraemia reduction targets are
JAMA internal medicine, December 21, 2018                   challenging but, in West Wales, this was the key
                                                            infection surrogate measure set by the local health
Although corticosteroids are widely used for adults
                                                            board in 2013, prior to the introduction of a Welsh
with sepsis, both the overall benefit and potential risks
                                                            Government target. The initial plateau of cases was
remain unclear. We conducted a systematic review and
                                                            not maintained and prompted this review. Success in
meta‐analysis of the efficacy and safety of
                                                            one area (sepsis management) conflicts with 'failure' in
corticosteroids in patients with sepsis. The findings
                                                            reducing E. coli bacteraemia. It is argued that targets
suggest that administration of corticosteroids is
                                                            need to be considered carefully in the light of all
associated with reduced 28‐day mortality compared
with placebo use or standard supportive care. More
research is needed to associate personalized medicine
with the corticosteroid treatment to select suitable
                                                            Sepsis: Early Recognition and Optimized Treatment.
patients who are more likely to show a benefit.
                                                            Kim, H.I. et al

                                                            Tuberculosis and respiratory diseases, January 2019
Identification of subclasses of sepsis that showed
                                                            Vol.82(1), pp.6‐14
different clinical outcomes and responses to amount of
fluid resuscitation: a latent profile analysis.             Sepsis is a life‐threatening condition caused by
                                                            infection and represents a substantial global health
Zhang, Z. et al
                                                            burden. Recent epidemiological studies showed that
Critical care (London, England), December 18, 2018,         sepsis mortality rates have decreased, but that the
Vol.22(1), p.347                                            incidence has continued to increase. Although a
                                                            mortality benefit from early‐goal directed therapy
Sepsis is a heterogeneous disease and identification of
                                                            (EGDT) in patients with severe sepsis or septic shock
its subclasses may facilitate and optimize clinical
                                                            was reported in 2001, three subsequent multicenter
management. This study aimed to identify subclasses of
                                                            randomized studies showed no benefits of EGDT
sepsis and its responses to different amounts of fluid
                                                            versus usual care. Nonetheless, the early
resuscitation. The study identified four subphenotypes
                                                            administration of antibiotics and intravenous fluids is
of sepsis, which showed different mortality outcomes
                                                            considered crucial for the treatment of sepsis. In 2016,
and responses to fluid resuscitation. Prospective trials
                                                            new sepsis definitions (Sepsis‐3) were issued, in which
are needed to validate our findings.
                                                            organ failure was emphasized and use of the terms
                                                            “systemic inflammatory response syndrome” and
                                                            “severe sepsis” was discouraged. However, early
Effect of cytomegalovirus reactivation on the time          detection of sepsis with timely, appropriate
course of systemic host response biomarkers in              interventions increases the likelihood of survival for
previously immunocompetent critically ill patients with     patients with sepsis. Also, performance improvement
sepsis: a matched cohort study.                             programs have been associated with a significant
van de Groep, K. et al                                      increase in compliance with the sepsis bundles and a
                                                            reduction in mortality. To improve sepsis management
Critical care (London, England), December 18, 2018,         and reduce its burden, in 2017, the World Health
Vol.22(1), p.348                                            Assembly and World Health Organization adopted a
Cytomegalovirus (CMV) reactivation in previously            resolution that urged governments and healthcare
immunocompetent critically ill patients is associated       workers to implement appropriate measures to
with increased mortality, which has been hypothesized       address sepsis. Sepsis should be considered a medical
to result from virus‐induced immunomodulation.
Therefore, we studied the effects of CMV reactivation
on the temporal course of host response biomarkers in        emergency, and increasing the level of awareness of
patients with sepsis. CMV reactivation was not               sepsis is essential.
independently associated with changes in the temporal
trends of host response biomarkers in comparison with
non‐reactivating patients. Therefore, these markers          Low D‐dimer levels in sepsis: Good or bad?
should not be used as surrogate clinical endpoints for
interventional studies evaluating anti‐CMV therapy.          Semeraro, F. et al

                                                             Thrombosis research, Vol.174, pp.13‐15 December 5,
APRIL and sTACI could be predictors of multiorgan
dysfunction syndrome in sepsis.                              DIC is a serious complication of sepsis and increases
                                                             the risk of death. D‐dimer (DD) is the most used fibrin‐
Lendak, D.F. et al                                           related marker for DIC diagnosis. However, DD levels
                                                             depend on both coagulation and fibrinolysis. Patients
Virulence, December 31, 2018, Vol.9(1), pp.946‐953
                                                             with severe sepsis and normal DD were shown to have
Although the role of B cells in sepsis immunoregulation      the highest mortality. Allegedly, normal DD in sepsis
has become an interesting topic, there is lack of data       masks a DIC form with strong fibrinolysis inhibition.
on the role of B cell function regulators in prediction of   Letter
multiorgan dysfunction syndrome (MODS). The aim of
this study was to evaluate the prognostic value of A
Proliferation Inducing Ligand (APRIL) and soluble            Effects of antiplatelet therapy on the mortality rate of
Transmembrane Activator and CAML Interactor Protein          patients with sepsis: A meta‐analysis.
(sTACI), the main B cell function regulators, in
prediction of MODS development within the first 48h          Ouyang, Y. et al
after admission to intensive care unit, among septic         Journal of critical care, Vol.50, pp.162‐168 December
patients. Elevated level of sTACI could be the alarm for     5, 2018
the increased B cell apoptosis and development of
immune paralysis. Including these biomarkers into            Abnormal platelet activation plays an important role in
predictive scores specific for septic patients may           the development of sepsis. The effect of antiplatelet
potentially improve their sensitivity and specificity.       drugs on the outcome of patients with sepsis remains
Measurement of their concentrations dynamics could           unclear. This meta‐analysis aimed to determine the
contribute to better assessment of sepsis evolution and      effect of antiplatelet drugs on the prognosis of
timely introduction of immunomodulatory therapy.             patients with sepsis. Antiplatelet drugs, particularly
                                                             aspirin, could be used to effectively reduce mortality in
                                                             patients with sepsis.
Circulating adrenomedullin estimates survival and
reversibility of organ failure in sepsis: the prospective
observational multinational Adrenomedullin and               Doppler‐defined pulmonary hypertension in sepsis and
Outcome in Sepsis and Septic Shock‐1 (AdrenOSS‐1)            septic shock.
study.                                                       Vallabhajosyula, S. et al
Mebazaa, A. et al                                            Journal of critical care, December 8, 2018, Vol.50,
Critical care (London, England), December 21, 2018,          pp.201‐206
Vol.22(1), p.354                                             The association of pulmonary hypertension (PH) in
Adrenomedullin (ADM) regulates vascular tone and             patients with sepsis is lesser understood. In patients
endothelial permeability during sepsis. Levels of            with sepsis and septic shock, PH is common and is
circulating biologically active ADM (bio‐ADM) show an        noted to be associated with higher short and long‐
inverse relationship with blood pressure and a direct        term mortality. Further studies are needed to
relationship with vasopressor requirement. In the            understand the mechanisms by which PH is associated
present prospective observational multinational              with outcomes.
Adrenomedullin and Outcome in Sepsis and Septic
Shock 1 (, AdrenOSS‐1) study, we assessed relationships
                                                                      An electronic warning system helps reduce the time to
between circulating bio‐ADM during the initial
                                                                      diagnosis of sepsis.
intensive care unit (ICU) stay and short‐term outcome
in order to eventually design a biomarker‐guided                      Westphal, G. A. et al
randomized controlled trial. AdrenOSS‐1 shows that
early levels and rapid changes in bio‐ADM estimate                    Revista Brasileira de terapia intensiva, December 13,
short‐term outcome in sepsis and septic shock. These                  2018
data are the backbone of the design of the biomarker‐                 To describe the improvements of an early warning
guided AdrenOSS‐2 trial.                                              system for the identification of septic patients on the
                                                                      time to diagnosis, antibiotic delivery, and mortality.
                                                                      This was an observational cohort study that describes
                                                                      the successive improvements made over a period of
                                                                      10 years using an early warning system to detect
                                                                      sepsis, including systematic active manual surveillance,
                                                                      electronic alerts via a telephonist, and alerts sent
                                                                      directly to the mobile devices of nurses. For all
                                                                      periods, after an alert was triggered, early treatment
                                                                      was instituted according to the institutional sepsis
                                                                      guidelines. Electronic systems help reduce the triage‐
                                                                      to‐diagnosis time and diagnosis‐to‐antibiotic time in
                                                                      patients with sepsis.

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